EP1858527A1 - Formes de dosage oral de derives de gemcitabine - Google Patents
Formes de dosage oral de derives de gemcitabineInfo
- Publication number
- EP1858527A1 EP1858527A1 EP06716760A EP06716760A EP1858527A1 EP 1858527 A1 EP1858527 A1 EP 1858527A1 EP 06716760 A EP06716760 A EP 06716760A EP 06716760 A EP06716760 A EP 06716760A EP 1858527 A1 EP1858527 A1 EP 1858527A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gemcitabine
- dosage form
- oral dosage
- pharmaceutical acceptable
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to oral dosage forms of certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (Gemcitabine).
- the present invention relates to the use of the said gemcitabine derivatives or a pharmaceutical acceptable salt thereof for preparing an oral dosage form ameliorating compliance in treatment of cancer.
- Gemcitabine has the formula:
- R 1 , R 2 and R 3 are independently selected from hydrogen and C 18 - and C 2 o- saturated and monounsaturated acyl groups, with the proviso that R 1 , R 2 and R 3 cannot all be hydrogen.
- gemcitabine is a well known cytostatic compound, marketed under the trade name Gemzar by Eli Lilly & Co.
- Gemzar is administered intravenously (i.v.).
- the reason for choosing a parenteral administration route is due to the toxicity of gemcitabine.
- gemcitabine Like a lot of drugs, it obviously would have been desirable to be able to administer gemcitabine orally.
- oral administration usually is much more pleasant than intravenous administration.
- R 1 , R 2 and R 3 are independently selected from hydrogen and C 18 - and C 2 o- saturated and monounsaturated acyl groups, with the proviso that R 1 , R 2 and R 3 cannot all be hydrogen or a pharmaceutical acceptable salt thereof, for preparing an oral dosage form ameliorating compliance in treatment of cancer, is provided.
- Gemcitabine has three derivatisable functions, namely the 5'- and 3'-hydroxyl groups and the N 4 -amino group. Each group can selectively be transformed into an ester or amide derivative, but di-adducts (di-esters or ester-amides) and tri-adducts may be formed as well. In the case of the di- and tri-adducts the acyl substituent groups need not necessarily be the same.
- the mono-acyl derivatives of this invention i.e. with two of R 1 , R 2 and R 3 being hydrogen, are preferred. It is especially preferred that the monosubstitution with the acyl group should be in the 3'-0 and 5'-O positions of the sugar moiety, with 5'-0 substitution being most preferred.
- the double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.
- the position of the double bond in the monounsaturated acyl groups also seem to affect the activity.
- esters or amides having their unsaturation in the ⁇ -9 position.
- the position ⁇ of the double bond of a monounsaturated fatty acid is counted from the terminal methyl group, so that, for example, eicosenoic acid (C 2 o: 1 ⁇ -9) has 20 carbon atoms in the chain and a single double bond is formed between carbon 9 and 10 counting from the methyl end of the chain.
- Esters, ester-amides and amides of gemcitabine derived from stearic acid (C 18 :0) and eicosanoic acid (C 2O ⁇ O) are advantageously used in some cases.
- elaidic acid (5')-gemcitabine ester for preparing an oral dosage form ameliorating compliance in treatment of cancer.
- the present invention relates to an oral dosage form useful for ameliorating compliance in treatment of cancer, comprising a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof.
- the present invention also provides a method for ameliorating compliance in treatment of cancer, in a subject in need of such treatment, which comprises orally administering to such subject a therapeutically effective amount of a gemcitabine derivative of formula (T) as defined in claim 1 or a pharmaceutical acceptable salt thereof.
- terapéuticaally effective amount refers to from about 0,1 mg to 20 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof, more preferred from about 100 mg to 2 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof, in a formulation containing 0,001 - 100% of the said derivative or salt thereof formulated in capsule, tablet, mixture, colloidal suspension or others for oral administration.
- a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof in a formulation containing 0,001 - 100% of the said derivative or salt thereof formulated in capsule, tablet, mixture, colloidal suspension or others for oral administration.
- Fig. 1 shows antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine in colon cancer xenograft Co5776.
- Fig. 2 shows antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine after intraperitoneal administration to mice with human colon cancer xenograft Co6044.
- Fig. 3 shows oral effect of elaidic acid (5')-gemcitabine ester in Co6044 xenograft.
- Fig. 4 shows mean body weight of treated animals.
- the maximum tolerated dose for gemcitabine is approximately 120 mg/kg per injection compared to 40 mg/kg per injection for elaidic acid (5')-gemcitabine ester. This is shown below by the experiments presented in table 1 and table 2 using different mice strains and also different human colon xenografts.
- BWC body weight change
- T/C volume of treated tumour versus volume of control tumour
- Ncr nu/nu female mice, 8 per group, were inserted with the human colon cancer xenograft Co6044 and treated IP every third day for five times with elaidic acid (5')- gemcitabine ester (40mg/kg) or gemcitabine (120 mg/kg) . Treatment started when the tumours reached a mean volume of 100 mm 3 . Excellent antitumor effect was obtained for elaidic acid (5')-gemcitabine ester and gemcitabine.
- Antitumour activity after oral administration of elaidic acid (5')-gemcitabine ester and gemcitabine was tested for the first time in NCR:nu/nu mice. The lowest starting dose was selected based on IP data. A dose of gemcitabine that is well tolerated and active when administered intraperitoneally (120 mg/kg per injection) was highly toxic and it was impossible to evaluate antitumour activity as gemcitabine was toxic at all tested doses. On the contrary and to our great surprise, a dose of elaidic acid (5')-gemcitabine ester (40 mg/kg) that was shown to be highly active after intraperitoneal administration was also highly active and tolerable when given orally. These results are shown in Table 3.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO20051467A NO322682B1 (no) | 2005-03-18 | 2005-03-18 | Anvendelse av gemcitabinderivater for fremstilling av orale doseringsformer ved kreftbehandling, samt slike orale doseringsformer |
PCT/NO2006/000085 WO2006098628A1 (fr) | 2005-03-18 | 2006-03-07 | Formes de dosage oral de derives de gemcitabine |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1858527A1 true EP1858527A1 (fr) | 2007-11-28 |
EP1858527A4 EP1858527A4 (fr) | 2010-10-27 |
Family
ID=35267108
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06716760A Withdrawn EP1858527A4 (fr) | 2005-03-18 | 2006-03-07 | Formes de dosage oral de derives de gemcitabine |
Country Status (13)
Country | Link |
---|---|
US (1) | US20080280851A1 (fr) |
EP (1) | EP1858527A4 (fr) |
JP (1) | JP2008533135A (fr) |
KR (1) | KR20070120539A (fr) |
AU (1) | AU2006223757A1 (fr) |
CA (1) | CA2600399A1 (fr) |
IL (1) | IL185866A0 (fr) |
NO (1) | NO322682B1 (fr) |
NZ (1) | NZ561377A (fr) |
RU (1) | RU2007138582A (fr) |
UA (1) | UA90893C2 (fr) |
WO (1) | WO2006098628A1 (fr) |
ZA (1) | ZA200707979B (fr) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8497292B2 (en) * | 2005-12-28 | 2013-07-30 | Translational Therapeutics, Inc. | Translational dysfunction based therapeutics |
WO2010039039A1 (fr) * | 2008-10-03 | 2010-04-08 | Clavis Pharma Asa | Formulations orales de dérivés de gemcitabine |
CN101525361B (zh) | 2009-04-21 | 2010-11-17 | 济南圣鲁金药物技术开发有限公司 | 基于吉西他滨结构的前药及其合成方法及应用 |
GB0907551D0 (en) | 2009-05-01 | 2009-06-10 | Univ Dundee | Treatment or prophylaxis of proliferative conditions |
JP6049712B2 (ja) | 2011-07-08 | 2016-12-21 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒルThe University Of North Carolina At Chapel Hill | 抗癌治療及び画像化並びに骨障害治療のための金属ビスホスホネートナノ粒子 |
CN102432654A (zh) * | 2011-09-26 | 2012-05-02 | 宋云龙 | 吉西他滨酰胺衍生物及其制备方法和用途 |
EP2919790B1 (fr) | 2012-11-13 | 2018-04-04 | Boyen Therapeutics, Inc. | Promédicaments de la gemcitabine et utilisations |
US10517822B2 (en) | 2013-11-06 | 2019-12-31 | The University Of Chicago | Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers |
US10463684B2 (en) | 2014-01-29 | 2019-11-05 | Board Of Regents, The Uneversety Of Texas System | Nucleobase analogue derivatives and their applications |
US11246877B2 (en) | 2016-05-20 | 2022-02-15 | The University Of Chicago | Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof |
CN107184592A (zh) * | 2017-05-17 | 2017-09-22 | 广东艾时代生物科技有限责任公司 | 吉西他滨在制备治疗类风湿性关节炎药物中的应用 |
US11826426B2 (en) | 2017-08-02 | 2023-11-28 | The University Of Chicago | Nanoscale metal-organic layers and metal-organic nanoplates for x-ray induced photodynamic therapy, radiotherapy, radiodynamic therapy, chemotherapy, immunotherapy, and any combination thereof |
CN112135634A (zh) | 2018-02-02 | 2020-12-25 | 马福瑞克斯肿瘤学股份有限公司 | 单磷酸吉西他滨的小分子药物偶联物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1327358C (fr) * | 1987-11-17 | 1994-03-01 | Morio Fujiu | Derives fluorocytidine |
AU720451B2 (en) * | 1997-01-24 | 2000-06-01 | Conpharma As | Gemcitabine derivatives |
WO2004041203A2 (fr) * | 2002-11-04 | 2004-05-21 | Xenoport, Inc. | Promedicaments de gemcitabine, leurs compositions pharmaceutiques et leurs utilisations |
-
2005
- 2005-03-18 NO NO20051467A patent/NO322682B1/no not_active IP Right Cessation
-
2006
- 2006-03-07 EP EP06716760A patent/EP1858527A4/fr not_active Withdrawn
- 2006-03-07 KR KR1020077023828A patent/KR20070120539A/ko not_active Application Discontinuation
- 2006-03-07 NZ NZ561377A patent/NZ561377A/en not_active IP Right Cessation
- 2006-03-07 WO PCT/NO2006/000085 patent/WO2006098628A1/fr active Application Filing
- 2006-03-07 JP JP2008501829A patent/JP2008533135A/ja active Pending
- 2006-03-07 RU RU2007138582/15A patent/RU2007138582A/ru not_active Application Discontinuation
- 2006-03-07 UA UAA200711518A patent/UA90893C2/ru unknown
- 2006-03-07 US US11/908,364 patent/US20080280851A1/en not_active Abandoned
- 2006-03-07 CA CA002600399A patent/CA2600399A1/fr not_active Abandoned
- 2006-03-07 AU AU2006223757A patent/AU2006223757A1/en not_active Abandoned
-
2007
- 2007-09-10 IL IL185866A patent/IL185866A0/en unknown
- 2007-09-17 ZA ZA200707979A patent/ZA200707979B/xx unknown
Non-Patent Citations (3)
Also Published As
Publication number | Publication date |
---|---|
NZ561377A (en) | 2009-10-30 |
CA2600399A1 (fr) | 2006-09-21 |
RU2007138582A (ru) | 2009-04-27 |
ZA200707979B (en) | 2008-11-26 |
NO20051467D0 (no) | 2005-03-18 |
EP1858527A4 (fr) | 2010-10-27 |
US20080280851A1 (en) | 2008-11-13 |
NO322682B1 (no) | 2006-11-27 |
IL185866A0 (en) | 2008-01-06 |
UA90893C2 (ru) | 2010-06-10 |
AU2006223757A1 (en) | 2006-09-21 |
KR20070120539A (ko) | 2007-12-24 |
WO2006098628A1 (fr) | 2006-09-21 |
JP2008533135A (ja) | 2008-08-21 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
Effective date: 20070921 |
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AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: ERIKSEN, OLE, HENRIK Inventor name: MYHREN, FINN Inventor name: SANDVOLD, MARIT, LILAND |
|
DAX | Request for extension of the european patent (deleted) | ||
A4 | Supplementary search report drawn up and despatched |
Effective date: 20100929 |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 20110429 |